Discovery and preliminary SAR studies of a novel, nonsteroidal progesterone receptor antagonist pharmacophore

Article abstract of DOI:10.1021/jm9801915

A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells. The lead compound LG001447 (1,2-dihydro- 2,2,4-trimethyl-6-phenylqu

Full text of DOI:10.1021/jm9801915

J . Med. Chem. 1998, 41, 3461-3466
3461
Discover y a n d P r elim in a r y SAR Stu d ies of a Novel, Non ster oid a l P r ogester on e
Recep tor An ta gon ist P h a r m a cop h or e
Charlotte L. F. Pooley,*,† J ames P. Edwards,† Mark E. Goldman,‡,| Ming-Wei Wang,§, Keith B. Marschke,‡
Diane L. Crombie,§ and Todd K. J ones†,∇
Departments of Medicinal Chemistry, New Leads Discovery, and Endocrine Research,
Ligand Pharmaceuticals Inc., San Diego, California
Received March 27, 1998
A series of 6-aryl-1,2-dihydro-2,2,4-trimethylquinolines was synthesized and tested for functional
activity on the human progesterone receptor isoform B (hPR-B) in mammalian (CV-1) cells.
The lead compound LG001447 (1,2-dihydro-2,2,4-trimethyl-6-phenylquinoline) was discovered
via directed high throughput screening of a defined chemical library utilizing an hPR-B
cotransfection assay. Electron-withdrawing substituents at the meta position of the C(6) aryl
group afforded substantial improvements in hPR modulatory activity. Several analogues were
able to potently block the effects of progesterone in vitro. Two compounds, 10 (LG120753)
and 11 (LG120830) with potencies comparable or equal to the steroidal hPR antagonist
onapristone (ZK98,299), were demonstrated to act as antiprogestins in vivo after oral
administration to rodents. This is the first disclosure of orally active nonsteroidal anti-
progestins.
In tr od u ction
We have been engaged in the discovery of nonsteroi-
dal progesterone receptor modulators.1 To date there
have been few classes of nonsteroidal progesterone
receptor modulators reported, and none have reached
the clinic,2 although steroidal hPR antagonists, typified
by mifepristone3 (1, RU486) and onapristone4 (2, ZK98,-
299), have been studied clinically. The potential uses
for antiprogestins include therapies for various gyne-
cological diseases,5 and nonsteroidal antiprogestins
might be expected to display novel pharmacology.6
Using a high throughput hPR-B screen,7,8 a nonsteroidal
antiprogestin lead from Ligand’s defined chemicals
collection was discovered9 (3, Figure 1). This article
discloses preliminary structure-activity relationship
studies of a series of nonsteroidal hPR-B antagonists
based on the 1,2-dihydro-2,2,4-trimethyl-6-phenylquino-
line pharmacophore, 3. Whereas previous studies of
nonsteroidal progesterone receptor antagonists have
failed to demonstrate oral activity in vivo,1,2 two of the
novel antiprogestins presented here have definitive anti-
progestational effects when dosed orally to rodents.
F igu r e 1. Mifepristone (1), onapristone (2), and LG001447
(3).
Ch em istr y
The initial lead, LG001447 (3), was screened for
activity on various intracellular receptors.10 It was
found to exhibit modest (IC50 ) 783 nM) antagonist
activity on hPR-B, and was selected for preliminary SAR
investigations. To efficiently examine the effect of C(6)-
aryl substitution on the biological activity of this novel
pharmacophore, we chose the boronic acid 6 as an
advanced intermediate. The synthesis of 6 and 8-13
is depicted in Scheme 1. Thus, treatment of 4-bromoa-
niline (4) with acetone and iodine, a process recognized
as the Skraup reaction,11 afforded the dihydroquinoline
5 in modest yield. Protection of N-1 as a tert-butylcar-
bamate followed by lithium-halogen exchange and
treatment with trimethylborate afforded the key inter-
mediate, boronic acid 6. A palladium-catalyzed (Su-
zuki12) cross-coupling of 6 with various aryl bromides
7, followed by removal of the t-butoxycarbonyl group
with trifluoroacetic acid afforded the dihydroquinolines
8-13 in acceptable overall yields (Scheme 1).
* Address correspondence to this author at Ligand Pharmaceuticals,
10275 Science Center Drive, San Diego, CA 92121. Tel: (619) 550-
7568. Fax: (619) 550-7249. E-mail: cdeckhut@ligand.com.
† Department of Medicinal Chemistry.
‡ New Leads Discovery.
§ Department of Endocrine Research.
| Current Address: Axiom Biotechnologies, 3550 General Atomics
Court, San Diego, CA 92121.
Current Address: GC BioTechnologies, LLC, 11099 N. Torrey
Pines Road, La J olla, CA, 92037.
∇ Current address: Ontogen Corporation, 2325 Camino Vida Roble,
Carlsbad, CA 92009.
S0022-2623(98)00191-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/01/1998

3462 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Pooley et al.
Sch em e 1a
onapristone blocks implantation and, hence, the estab-
lishment of pregnancy.14 The effects of oral administra-
tion of onapristone (2) to mated females is depicted in
Figure 2. Although doses of 0.5 or 1.0 mg/mouse of 2
had little effect, a dose of 2.5 mg/mouse completely
blocked implantation in these animals.
Compounds 10 (LG120753) and 11 (LG120830) were
also tested in this assay and the results are depicted in
Figures 3 and 4, respectively. Oral administration of
10 blocked implantation in a dose-dependent manner
(Figure 3). The 100% efficacious dose of 5.0 mg/mouse
indicates that 10 is 2-fold less potent than 2 in vivo.
Compound 11 (Figure 4) was 100% efficacious at 2.5 mg/
mouse, which is equivalent in potency and efficacy to
onapristone (2). Although 10 and 11 are 10-fold less
potent than 2 in vitro (Table 1), the comparable activity
in vivo may be due to favorable pharmacokinetic or
pharmacodynamic characteristics. This is the first
definitive demonstration of in vivo antiprogestational
activity by a nonsteroidal hPR ligand following oral
administration. Additionally, this is the first report of
a nonsteroidal compound that has been shown to have
activity equipotent to a known leading steroidal anti-
progestin. Although no overt signs of toxicity were
observed, hepatomegaly was noted in the test animals,
especially in the high-dose groups.15
a(a) Acetone, iodine (4 mol %), reflux (30%). (b) (i) n-BuLi (1.1
equiv), THF, -78 °C, then di-tert-butyl dicarbonate (1.5 equiv)
(67%); (ii) t-BuLi (2.5 equiv), THF, -78 °C, then (MeO)3B (40-
50%). (c) (i) ArBr (7) (1 equiv), 50% EtOH/toluene, K2CO3 (2 equiv),
(Ph3P)4Pd (5-10 mol %), reflux; (ii) excess trifluoroacetic acid (30-
70% for 2 steps).
Biologica l Activities
The in vitro biological activities on hPR of 3 and 8-13
are depicted in Table 1 along with data for the steroidal
hPR antagonists 1 and 2 for comparison. The parent
compound 3 was a 783 nM antagonist on hPR-B in the
cotransfection assay and displayed moderate (Ki ) 133
nM) affinity for hPR-A (entry 3). Although the addition
of a C(3′)-fluoro substituent to the C(6)-aryl moiety of 3
did not affect the hPR activity (8, entry 4), C(3′)-C(5′)-
difluoro substitution resulted in an order of magnitude
improvement of activity in both the functional and
binding assays (9, entry 5). The monosubstituted C(3′)-
cyano compound 10 (entry 6) was a potent antagonist
on hPR-B; the addition of a C(5′)-fluoro substituent to
10 had only a small effect on in vitro activity (11, entry
7). A C(3′)-nitro group also imparted potent hPR-B
antagonist activity (12), while the C(5′)-fluoro-C(3′)-nitro
compound 13 had comparable in vitro activity. Notably,
the binding affinity of 13 for baculovirus-expressed
hPR-A (Ki ) 5 nM) was comparable to that of the
natural hormone, progesterone (Ki ) 3 nM).
A limitation to the use of the steroidal PR antagonists
mifepristone and onapristone is their significant cross-
reactivities on hAR and hGR. These novel nonsteroidal
PR antagonists displayed limited cross-reactivity with
hGR and hAR; LG120753 (10) and LG120830 (11) were
5- to 7-fold less potent on hAR and greater than 20-fold
less potent on hGR, hER, and hMR. These results
indicate favorable cross-reactivity profiles for this phar-
macophore compared with those of the known steroids
(Table 2).
To verify that the antifertility effects of 11 were due
to its antiprogestational activity, an infertility reversal
experiment was performed (Figure 5). Co-administra-
tion of 11 (2.5 mg/mouse orally) and the known steroidal
progestin R502016 (1.0 mg/animal subcutaneously) re-
sulted in a 100% pregnancy rate, demonstrating that,
like mifepristone (1), the antifertility effects of 11 could
be reversed by progestin supplementation. A similar
experiment was performed testing compound 10 com-
bined with R5020. The results (not shown) were
comparable to that of compound 11. These results
verify that the antifertility effects of 10 and 11 are due
to antiprogestational activity rather than toxicity.
Con clu sion
These studies demonstrate for the first time that
nonsteroidal compounds can act as antagonists of the
human progesterone receptor with activities comparable
to those of known steroidal hPR antagonists. Due to
the novel structure class differing from the steroid core,
it has been shown that these compounds are favorably
less active on the other steroid receptors (hAR, hER,
hMR, and hGR) thus making them more selective for
the target hPR. Since one of the major problems with
steroid therapies is cross-reactivity, we view this as an
important feature of these compounds.
It has been demonstrated that the in vitro effects can
be verified using a known rodent model. This is the first
time a new, nonsteroidal pharmacophore has demon-
strated oral activity in vivo as an antagonist on the
progesterone receptor. Further, the pharmacological
effects of one of these nonsteroidal hPR antagonists (11,
LG120830) was shown to be equivalent to onapristone
(2) in a mouse antifertility model using oral administra-
tion.17
The in vitro antiprogestational effects of several of
these nonsteroidal hPR antagonists were then verified
using animal models. A definitive in vivo assay for
progestational effects is the implantation assay. Im-
plantation is the process by which the blastocyst be-
comes attached to the endometrium of the uterus, and
this process is regulated by progestins.13 In this model,
oral dosing of antiprogestins such as mifepristone or
The antifertility effects of 10 and 11 were completely
reversed by co-administration of the steroidal progestin

SAR Studies of Nonsteroidal hPR Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3463
Ta ble 1. In Vitro hPR-B Activity in Cotransfected CV-1 Cells and Binding Affinities to Baculovirus-Expressed hPR-Aa
hPR-B activity
b
entry
ligand
R1
mifepristone
onapristone
R2
IC50 (nM)
efficacyc (%)
hPR-A activity, Kib (nM)
1
2
3
4
5
6
7
8
9
1
2
3
8
9
10
11
12
13
0.30 ( 0.04
2.2 ( 0.4
783 ( 162
750
99 ( 0
95 ( 1
72 ( 4
94
85 ( 6
81 ( 2
82 ( 3
83 ( 1
78 ( 2
1.1 ( 0.32
18 ( 33
133 ( 71
182
10 ( 2
19 ( 3
10 ( 1
20 ( 2
5 ( 2
H
F
F
H
H
F
79 ( 43
CN
CN
NO2
NO2
H
F
H
F
38 ( 6
30 ( 4
42 ( 6
70 ( 18
a
b
Cotransfection experimental values represent at least triplicate determinations. Values are in nM, mean ( SEM, N g 2. If no SEM
is noted, the value is from a single determination. IC50 values represent the concentration required to give half maximal inhibition for
that ligand. c Efficacy expressed as percent relative to maximal inhibition (e.g, no agonist) ) 100%.
Ta ble 2. Antagonist Cross-Reactivities of Nonsteroidal PR Antagonists and Steroidal Antagonist Standards on hAR, hER, hGR, and
hMRa
hAR
hER
hGR
hMR
ligand
potency (nM) efficacy (%) potency (nM) efficacy (%) potency (nM) efficacy (%) potency (nM) efficacy (%)
mifepristone
(1)
onapristone
(2)
LG120753
(10)
LG120830
(11)
5 ( 2
269 ( 57
227 ( 63
210a
7 ( 2
93 ( 4
86 ( 2
88a
>1000
>1000
>1000
>1000
40 ( 7
27 ( 4
0.8 ( 0.1
27 ( 4
98 ( 1
100 ( 0
7 ( 18
<20
>1000
>1000
>1000
>1000
77 ( 5
34 ( 9
94 ( 1
80 ( 2
<20
<20
>1000
>1000
a
Antagonist efficacies were determined as a function (%) of maximal inhibition in the presence of an EC50 concentration of DHT,
estradiol, dexamethasone, or aldosterone for hAR, hER, hGR, and hMR, respectively; potencies ) IC50 values. Values represent the mean
( SEM of at least two independent experiments except where indicated (a ) 1).
F igu r e 2. Effect of 2 (mg/mouse) on mouse implantation when
F igu r e 3. Effect of 10 (mg/mouse) on mouse implantation
given orally once daily for three days (day 2-4 of pregnancy).
when given orally once daily for three days (day 2-4 of
Virgin female mice were caged with fertile males overnight
pregnancy). Virgin female mice were caged with fertile males
and examined the next morning for vaginal plugs (day 1 of
overnight and examined the next morning for vaginal plugs
pregnancy). Mice (n g 6 per dose group) were treated orally
with 2 at 32, 46, and 80 h post coitus. Control animals (n )
11) received an equivalent volume of sesame oil. Necropsies
were performed on Day 8 post coitus, and the number of
implantation sites was recorded. ***P < 0.001 compared to
oil-treated group.
(day 1 of pregnancy). Mice were treated orally with 10 (0.1,
0.5, 1.0, 2.5, or 5.0 mg/animal) between day 2 and day 4 of
pregnancy. Control animals (n ) 10) received an equivalent
volume of sesame oil. Autopsies were carried out at day 8 of
pregnancy, and the number of implantation sites was recorded.
Number of animals per treatment group is given in parenthe-
ses. * ) P < 0.05; *** ) P < 0.001 vs control.
R5020, decisively demonstrating that the in vivo activi-
ties of 10 and 11 are specifically directed against
progesterone-mediated reproductive processes. These
studies provide the basis for the discovery of new
nonsteroidal progesterone receptor modulators to ad-
dress unmet clinical needs in the areas of female
reproductive oncology.
a reflux condenser attached to a Soxhlet apparatus was
charged with 4-bromoaniline, 4, (100 g, 581 mmol), catechol
(6.0 g, 39 mmol), iodine (5.0 g, 20 mmol), and acetone (1.5 L).
The Soxhlet apparatus contained oven-dried 4 Å sieves. The
mixture was warmed to reflux for 48 h at which point it was
cooled to room temperature. Celite (350 mL) was added,
followed by evaporation of the solvent to afford a powder that
was then applied to a silica gel column for purification. The
eluting solvent was 3% ethyl acetate in hexanes. Material
from the column was further purified by recrystallization in
warm hexanes to afford the pure product, 5 (28.7 g, 20%): 1H
Exp er im en ta l Section 18
6-Br om o-1,2-d ih yd r o-2,2,4-t r im et h ylq u in olin e (5).
A
2-L round-bottom flask equipped with a magnetic stir bar and

3464 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18
Pooley et al.
dicarbonate (3.85 g, 18 mmol) was added in one portion.
Note: a significant exotherm was observed upon the addition
of the dicarbonate (∼0-12 °C). The reaction was monitored
by TLC (50% ethyl acetate/methylene chloride) as it warmed
to room temperature until all of the intermediate (tert-butyl-
carboxycarbonyl-1,2-dihydro-2,2,4-trimethylquinoline) had been
consumed (3-5 h). The reaction mixture was quenched with
saturated ammonium chloride (100 mL) and partitioned
between ethyl acetate (100 mL). The organic layer was rinsed
two times with saturated ammonium chloride (50 mL each).
The organic layer was rinsed once with brine (100 mL). The
aqueous layers were combined and back-extracted with me-
thylene chloride (75 mL). The organic layers were combined
and dried over anhydrous sodium sulfate. The crude mixture
was purified by flash chromatography (400 mL silica, 2% ethyl
acetate/hexane); 3.8 g oil, 67%: 1H NMR (400 MHz, acetone-
d6) 7.30 ppm (s, 1H), 7.28 (d, J ) 8.0, 1H), 7.11 (d, J ) 8.0,
1H), 5.60 (s, 1H), 2.00 (s, 3H), 1.49 (s, 9H), 1.48 (s, 6H).
F igu r e 4. Effect of 11 (mg/mouse) on mouse implantation
when given orally once daily for three days (day 2-4 of
pregnancy). Virgin female mice were caged with fertile males
overnight and examined the next morning for vaginal plugs
(day 1 of pregnancy). Mice (n g 6 per dose group) were treated
orally with 11 at 32, 46, and 80 h post coitus. Control animals
(n ) 8) received an equivalent volume of sesame oil. Necropsies
were performed on day 8 post coitus, and the number of
implantation sites was recorded. ***P < 0.001 compared to
oil-treated group.
(1-ter t-b u t oxyca r b on yl-1,2-d ih yd r o-2,2,4-t r im et h yl-6-
qu in olin yl)-bor on ic Acid (6). A 25-mL round-bottom flask,
equipped with a magnetic stir bar, was charged with 6-bromo-
1-tert-butylcarboxycarbonyl-1,2-dihydro-2,2,4-trimethylquino-
line (3.77 g, 11 mmol) under nitrogen. The oil was dissolved
in 11 mL THF (anhydrous) and cooled to -78 °C. tert-
Butyllithium (12.6 mL, 21 mmol, 1.7 M) was added by syringe
over a period of 10 min (maintaining the temperature below
-70 °C) turning the reaction mixture from pale yellow to bright
yellow. The reaction was allowed to continue at -75 °C until
all of the starting material had been consumed as judged by
TLC (15% ethyl acetate/hexane). At that point, trimethyl
borate (30 mmol) was added by syringe over 5-10 min
(temperature between -70 °C and -65 °C). After the reaction
was monitored to completion, the product mixture was quenched
with saturated ammonium chloride (200 mL). After the
addition of ethyl acetate (200 mL), the mixture was partitioned
into two phases. The organic phase was rinsed two times with
saturated ammonium chloride (100 mL) and once with brine
(100 mL). The combined aqueous layers were back-extracted
with ethyl acetate (100 mL). The organic layers were com-
bined and dried over anhydrous sodium sulfate. The crude
mixture was applied to a small column containing 200 mL
silica and 10% ethyl acetate/hexane. The higher Rf impurities
were eluted with 2 L of 10% ethyl acetate/hexane. The boronic
acid, 3, was eluted off the column with 500 mL of ethyl acetate
followed by 750 mL of ethanol to provide 1.48 g (44%) of 6:
1H NMR (400 MHz, acetone-d6) 7.73 ppm (d, J ) 1.2, 1H), 7.66
(dd, J ) 8.0, 1.2, 1H), 7.13 (d, J ) 8.0, 1H), 5.49 (s, 1H), 2.01
(d, J ) 1.6, 3H), 1.50 (s, 9H), 1.46 (s, 6H).
Gen er a l Meth od . Bia r yl Su zu k i Cou p lin g of a n Ar yl
Br om id e w ith th e 6-Qu in olin ylbor on ic Acid (6). A 10-
mL recovery flask equipped with a magnetic stir bar was
charged with the aryl bromide (1.0 equiv) which was then
diluted with toluene (0.1 M). Tetrakis(triphenylphosphine)
palladium (1 mol percent), 6 (1.0 equiv in 0.1 M solution of
ethanol), and 2.0 M potassium carbonate (2 mol percent) were
added to the reaction flask sequentially under a nitrogen
atmosphere. A reflux condenser was fitted to the flask. The
cloudy, reddish solution was stirred rapidly and heated to
reflux for about 4 h until the starting material had been
completely consumed as judged by TLC (15% ethyl acetate/
hexane). The product mixture was then cooled to room
temperature and quenched with saturated ammonium chloride
(4-5 mL). Ethyl acetate (5 mL) was used to partition the
mixture. The organic layer was rinsed two times with
saturated ammonium chloride (5 mL each). The aqueous
layers were back-extracted with ethyl acetate (5 mL). The
organic layers were combined and dried over anhydrous
sodium sulfate. The crude mixture was isolated and applied
to a column (200 mL silica, 10% ethyl acetate/hexane).
F igu r e 5. Reversal of mifepristone (1) or LG120830 (11)
induced infertility by co-administration of R5020 for three days
(day 2-4 of pregnancy). Virgin female mice were caged with
fertile males overnight and examined the next morning for
vaginal plugs (day 1 of pregnancy). Mice (n ) 6 per dose group)
were treated orally with 1 (0.5 mg/animal) or 11 (2.5 mg/
animal) between day 2 and day 4 of pregnancy, accompanied
by three daily subcutaneous injections of R5020 (1.0 mg/
animal). Control animals (n ) 6) received an equivalent
volume of sesame oil. Necropsies were carried out on day 8 of
pregnancy, and the number of implantation sites was recorded.
** ) P < 0.01; ***P < 0.01 vs control.
NMR (400 MHz, acetone-d6) 7.06 ppm (d, J ) 4.0, 1H), 6.99
(dd, J ) 8.0, 4.0, 1H), 6.42 (d, J ) 8.0, 1H), 5.36 (s, 1H), 5.28
(br s, 1H) 1.92 (d, J ) 4.0, 3H), 1.24 (s, 6H).
6-Br om o-1-ter t-bu tyl-car boxycar bon yl-1,2-dih ydr o-2,2,4-
tr im eth ylqu in olin e. An oven-dried 250-mL round-bottom
flask equipped with a magnetic stirrer and an airtight nitrogen
inlet was charged with 5 (4.04 g, 16.0 mmol). The white
crystals were dissolved in 40 mL THF (anhydrous). The clear
solution was cooled to -78 °C with constant stirring.
A
thermocouple was used to monitor the internal reaction
temperature. n-Butyllithium (11.2 mL, 17 mmol, 1.5 M) was
added slowly by syringe over a period of 15 min (internal
temperature was maintained between -70 °C and -65 °C)
turning the reaction mixture bright yellow. The reaction was
allowed to continue stirring at -75 °C for an additional 15
min. The reaction was warmed to 0 °C, and the di-tert-butyl-
The purified material was charged to a 10-mL recovery
flask. Methylene chloride was added so that the residue was
completely dissolved (0.1 mL to 0.3 mL). The mixture was
cooled to 0 °C, and trifluoroacetic acid was added quickly by
syringe (∼40 equiv), turning the solution from colorless to dark

SAR Studies of Nonsteroidal hPR Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 18 3465
green/black. The progress of the reaction was monitored by
TLC (15% ethyl acetate/hexane) over 1 h until all the starting
material had been consumed.
1H), 6.59 (d, J ) 8.4, 1H), 5.37 (s, 2H), 2.04 (s, 3H), 1.28 (s,
6H); 13C NMR (acetone-d6) 145.5, 130.8, 130.5, 129.8, 129.7,
129.6, 128.8, 127.8, 126.7, 122.7, 121.9, 119.6, 113.9, 113.5,
52.5, 31.5, 18.8; IR (salt plate): 3371.8, 2965.3, 2917.8, 2226.9.
Anal. (C19H18N2) C, H, N.
3-Br om o-5-flu or oben zon itr ile. A 1-L round-bottom flask
equipped with a magnetic stir bar was charged with 1,3-
dibromo-5-fluorobenzene (44.0 g, 173 mmol), DMF (268 mL),
pyridine (28 mL), and copper(I) cyanide (15.5 g, 173 mmol)
under nitrogen. A reflux condenser was attached to the flask.
The green, cloudy mixture was stirred at reflux for 3 h. Once
lower Rf impurities were observed, the reaction was allowed
to cool to room temperature. The reaction mixture was
quenched with 200 mL of ether, and a precipitate formed in
the dark solution. The precipitate was gravity-filtered through
Celite. The filtrate was rinsed three times with ether (100
mL/50 g bromide). The isolated solution was added to a
separatory funnel. The organic layer was washed with a 2:1
mixture of water and concentrated ammonium hydroxide (200
mL), followed by saturated ammonium chloride solution (2 ×
200 mL) and saturated sodium bicarbonate (200 mL). The
aqueous layers were back-rinsed with ether (3 × 100 mL). The
organic layers were combined and dried over anhydrous
sodium sulfate. The product, 3-bromo-5-fluorobenzonitrile,
was purified by flash column chromatography (30 mL of silica,
hexane) followed by recrystallization from hexane: 1H NMR
(acetone-d6) 7.81 (s, 1H), 7.73 (dd, J ) 8.4, 1.9, 1H), 7.65 (dd,
J ) 8.5, 2.0, 1H).
1,2-Dih yd r o-6-p h en yl-2,2,4-tr im eth ylqu in olin e (3). In
a 300-mL pressure tube, a solution of 4-aminobiphenyl (2.40
g, 14.2 mmol) in acetone (130 mL) was treated with iodine (0.3
g). The tube was sealed and heated to 90 °C for 16 h. The
reaction mixture was allowed to cool to room temperature,
concentrated, and purified by silica gel chromatography (hex-
ane/EtOAc, 40:1) to afford 2.35 g (66%) 3 as a white solid, mp
103-104 °C: 1H NMR (acetone-d6) 7.56 (d, J ) 1.8, 1H), 7.43
(m, 3H), 7.23 (m, 2H), 6.58 (d J ) 8.1, 1H), 5.36 (s, 1H), 5.20
(br s, 1H), 2.04 (d, J ) 1.3, 3H), 1.28 (s, 6H); 13C NMR (acetone-
d6) 144.8, 142.6, 129.5, 129.0, 127.7, 126.7, 126.6, 122.7, 122.0,
113.9, 52.5, 31.4, 18.9; IR (salt plate) 3383.7, 2973.1. Anal.
(C18H19N) C, H, N.
1,2-D i h y d r o -6-(3-flu o r o p h e n y l)-2,2,4-t r i m e t h y l-
qu in olin e (8). This compound was prepared according to the
general method. From 6 (68.0 mg, 0.21 mmol) and com-
mercially available 3-fluorobromobenzene (40.1 mg, 0.18 mmol,
Lancaster) was isolated 8 (20.0 mg, 29%) which was purified
by reverse phase HPLC (ODS column, 97% methanol/water,
3.0 mL/min, retention time ) 9.14 min): 1H NMR (acetone-
d6) 7.32 (m, 5H), 6.95 (m, 1H), 6.58 (d, J ) 8.1, 1H), 5.37 (s,
1H), 5.31 (br s, 1H), 2.04 (d, J ) 1.1, 3H), 1.27 (s, 6H); 13C
NMR (acetone-d6) 164.2 (d, J C-F ) 242.8), 145.3, 145.2 (d, J C-F
) 7.8), 131.2, 131.1, 129.6, 128.9, 127.9, 127.9, 127.8, 122.8,
122.4, 122.4, 122.0, 113.9, 113.1, 113.0, 112.9, 112.8, 52.5, 31.5,
18.9. Anal. (C18H18FN) C, H, N.
6-(3,5-Diflu or op h e n yl)-1,2-d ih yd r o-2,2,4-t r im e t h yl-
qu in olin e (9). This compound was prepared according to the
general method. From 6 (59.7 mg, 0.19 mmol) and com-
mercially available 3,5-difluorobromobenzene (36.2 mg, 0.19
mmol, Lancaster) was isolated 9 (7.0 mg, 10%) which was
purified by reverse phase HPLC (ODS column, 97% methanol/
water, 3.0 mL/min): 1H NMR (acetone-d6) 7.35 (d, J ) 2.2,
1H), 7.28 (dd, J ) 8.2, 2.1, 1H), 7.20 (ddd, J ) 13.0, 4.3, 2.1,
2H), 6.80 (tt, J ) 9.1, 2.1, 1H), 6.57 (d, J ) 8.3, 1H), 5.43 (s,
1H), 5.37 (br s, 1H), 2.04 (d, J ) 1.1, 3H), 1.28 (s, 6H); 13C
NMR (acetone-d6) 164.5 (dd, J C-F ) 245.5, 14.5), 146.4 (t, J C-F
) 9.3), 145.9, 129.7, 128.9, 127.9, 126.6, 122.8, 121.9, 113.8,
109.1, 109.0 (d, J C-F ) 25.7), 108.9, 101.2 (t, J C-F ) 25.0), 52.6,
31.6, 18.8. Anal. (C18H17F2N) C, H, N.
6-(3-Cya n o-5-flu or op h en yl)-1,2-d ih yd r o-2,2,4-tr im eth -
ylqu in olin e (11). This compound was prepared according to
the general method from 6 (3.9 g, 12 mmol) and 3-bromo-5-
fluorobenzonitrile (2.5 g, 12 mmol). The product was purified
by recrystallization from hexane to afford the product (2.2 g,
53%), mp 127-129 °C: 1H NMR (acetone-d6) 7.83 (t, J ) 1.1,
1H), 7.67 (dt, J ) 10.2, 2.2, 1H), 7.42 (d, J ) 2.2, 1H), 7.38 (m,
1H), 7.35 (dd, J ) 9.0, 2.9, 1H), 6.58 (d, J ) 8.3, 1H), 5.52 (br
s, 1H), 5.38 (s, 1H), 2.04 (d, J ) 1.2, 3H), 1.28 (s, 6H); 13C NMR
(acetone-d6) 163.7 (d, J C-F ) 247.0), 146.3, (d, J C-F ) 26.6),
129.7, 128.8, 128.1, 126.2 (d, J C-F ) 3.0), 125.4 (d, J C-F ) 2.7),
123.0, 121.9, 118.6, 117.7 (d, J C-F ) 22.0), 116.2, (d, J C-F
)
25.0), 114.8, (d, J C-F ) 10.5), 113.9, 113.9, 52.7, 31.6, 31.6,
18.9; IR (salt plate) 3377.3, 2965.0, 2919.1, 2858.2, 2230.6.
Anal. (C19H17FN2) C, H, N.
1,2-Dih yd r o-6-(3-n it r op h en yl)-2,2,4-t r im et h ylq u in o-
lin e (12). This compound was prepared according to the
general method from compound 6 (19.4 mg, 0.06 mmol) and
commercially available 3-nitrobromobenzene (12.3 mg, 0.06
mmol). The product (2.9 mg, 16%) was isolated and purified
by flash column chromatography (75 mL silica, hexane to 5%
ethyl acetate/hexane) followed by reverse phase flash column
chromatography (50 mL ODS, 80% methanol/water): 1H NMR
(acetone-d6) 8.34 (t, J ) 1.8, 1H), 8.00 (ddd, J ) 25.2, 8.3, 2.1,
1H), 7.60 (t, J ) 8.0, 1H), 7.38 (d, J ) 2.1, 1H), 7.32 (dd, J )
8.4, 2.2, 1H), 6.60 (d, J ) 8.3, 1H), 5.42 (br s, 1H), 5.38 (s,
1H), 2.04 (s, 3H), 1.29 (s, 6H): 13C NMR (acetone-d6) 149.8,
145.8, 144.3, 132.6, 130.7, 129.7, 128.8, 128.0, 126.6, 122.8,
122.0, 120.9, 120.7, 114.0, 52.6, 31.6, 18.9. Anal. (C18H18N2O2)
C, H, N.
1,2-Dih yd r o-6-(5-flu or o-3-n it r op h en yl)-2,2,4-t r im et h -
ylqu in olin e (13). This compound was prepared according to
the general method from compound 6 (140 mg, 0.44 mmol) and
3-nitro-5-fluoroiodobenzene (117 mg, 0.44 mmol). The product
(95.0 mg, 69%) was isolated and purified by flash column
chromatography (150 mL silica, hexane to 20% acetone/
hexane) followed by second flash column chromatography (100
mL silica, hexane to 20% ethyl acetate/hexane), mp 167-169
°C: 1H NMR (acetone-d6) 8.21 (t, J ) 1.7, 1H), 7.78 (m, 2H),
7.43 (d, J ) 2.1, 1H), 7.37 (dd, J ) 8.4, 2.3, 1H), 6.60 (d, J )
8.3, 1H), 5.55 (br s, 1H), 5.40 (s, 1H), 2.04 (s, 3H), 1.29 (s, 6H);
13C NMR (acetone-d6) 163.7 (d, J C-F ) 246.8), 150.6 (d, J C-F
)
10.6), 146.3 (d, J C-F ) 8.9), 129.8, 128.8, 128.2, 125.3, 123.0,
122.0, 119.0 (d, J C-F ) 22.3), 116.8 (d, J C-F ) 2.6), 114.0, 108.2
(d, J C-F ) 26.5), 52.7, 52.6, 31.7, 31.6, 18.9; IR (salt plate)
3398.1, 2966.9. Anal. (C18H19FN2O2) C, H, N.
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